Radiopharmaceuticals
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____________________________________________________________ 3AQ20a ■ RADIOPHARMACEUTICALS Guideline Title Radiopharmaceuticals Legislative basis Directives 65/65/EEC, 75/318/EEC as amended, Directive 89/343/EEC Date of first adoption December 1990 Date of entry into June 1991 force Status Last revised December 1990 Previous titles/other None/III/3936/89 references Additional Notes This note for guidance concerns the application to radiopharmaceuticals of Directive 65/65/EEC and of parts 2, 3 and 4 of the Annex to Directive 75/318/EEC as amended, with a view to the granting of a marketing authorisation for a radiopharmaceutical. CONTENTS 1. INTRODUCTION 2. PHYSICO-CHEMICAL, BIOLOGICAL OR MICROBIOLOGICAL TESTS OF MEDICINAL PRODUCTS 3. TOXICOLOGICAL AND PHARMACOLOGICAL TESTS 4. CLINICAL DOCUMENTATION 5. RADIATION DOSIMETRY 6. LABELLING AND PACKAGING 175 ____________________________________________________________ 3AQ20a ■ RADIOPHARMACEUTICALS 1. INTRODUCTION Applications for marketing authorisation in respect of radiopharmaceuticals should be accompanied, as in the case of all medicinal products, by the particulars and documents referred to in Directives 65/65/EEC and 75/319/EEC, as amended, and in the Annex of Directive 75/318/EEC as amended. The provisions of Directive 89/343/EEC also apply. The relevant provisions of the European Pharmacopoeia should be observed. Due account must be taken of the other relevant CPMP guidelines. Most radiopharmaceuticals are used for the purpose of medical diagnosis. They are usually given only once, or sometimes on a few occasions, and contain only small amounts of the active substances with a radionuclide attached to them to allow scintigraphic imaging or measurement of biodistribution. Such radiopharmaceuticals do not often show any measurable pharmacodynamic effect. Radiation is a general property of all radiopharmaceuticals, which when administered give the patient an inevitable radiation dose. In the case of therapeutic radiopharmaceuticals, the radiation effect is the wanted property. Evaluation of the safety and efficacy of radiopharmaceuticals should include radiopharmaceutical and radiation hygiene aspects and radiation dosimetry in addition to general parameters. Radiopharmaceuticals have changing composition with time, associated with the radioactive decay. The physical half-life of the radionuclide is often so short that, in these cases, the final preparation has to be done immediately before administration to the patient; this leads to the use of semi-manufactured products such as radionuclide generators, precursors and kits. Evaluation of the safety and efficacy of radiopharmaceuticals is also concerned with the specifications of generators, kits and other semi-manufactured products. Specifications may also require special attention in cases where samples from the patient are labelled with a radioactive substance before readministration (precursor radiopharmaceuticals). When radiopharmaceuticals go directly from the generator to the patient (e.g. ultra short-lived radioactive gases), the consistency of the production process has a particularly great importance. This note for guidance covers the following products: – ready-for-use radiopharmaceuticals; – non-radioactive components (kits) for combination with a radioactive component (usually the eluate from a radionuclide generator); – radionuclide generators; – precursors used for radiolabelling other substances prior to administration (e.g. samples from patients). 177 ■ 3AQ20a ____________________________________________________________ 2. PHYSICO-CHEMICAL, BIOLOGICAL OR MICROBIOLOGICAL TESTS OF MEDICINAL PRODUCTS 2.1 Qualitative and quantitative particulars of the constituents and development pharmaceutics For the radionuclides, details must be given of their source, i.e. whether fission or target material is used. Radioactivity should be expressed in Bequerels at a given date, and hour in appropriate cases (other units may be added). If a calibration time is stated, the time zone used should be stated (e.g. GMT/CET). Where practicable, the proportion (specific activity, carrier free or carrier added) of inactive isotopes in the carrier should be stated. For radiopharmaceutical kits, any added compound (e.g. stannous salt for reduction of pertechnetate ions in the eluate from a technetium 99mTc generator) and manipulation essential for radiolabelling should be stated. Where applicable, evidence to confirm the efficacy and specificity of the radiolabelling of the labelling medium (e.g. 99mTc) should be supplied. A discussion of the necessary specification (e.g. purity, pH) of radiolabelling medium should be stated for kits. After radiolabelling, the compatibility of the product with the containers and closures should be considered and validated where appropriate. 2.2 Description of method of preparation Because of the complexity of the production of radiopharmaceuticals, it is important that methods for obtaining and maintaining sterility during manufacture (preparation and assembly) are adequately described. Information should be given on validation of those processes. a) Radiopharmaceutical kits: the instructions for final preparation should include: – minimum and maximum for both volume and amount of radioactivity to be added; – any special quality requirement for the radiolabelling medium; – the standing time and any other manipulation necessary during final preparation (detailed and justified); – details supporting recommendations on quality control procedures such as checking radiochemical purity of the prepared radiopharmaceutical prior to administration; – as relevant, data on stability of particles (e.g. of colloidal size) after reconstitution and justification for the quantity of added materials. These aspects should be discussed and documented adequately in the Development Pharmaceutics part of the dossier. b) Generators The recommendations for use of the generators should be discussed and documented. 178 ____________________________________________________________ 3AQ20a ■ c) Precursors The recommendations for use of the precursors should be discussed and documented. 2.3 Control of starting materials For the purposes of this section “starting materials” shall mean all the constituents of the medicinal product, if necessary, all the constituents of its containers and closures and where applicable, all constituents of the radionuclide source and any other materials used in the final process prior to administration. A full description is required of the separation of radionuclides and the control of radionuclide purity, as well as specific activity (with respect to impurities and degradation products). Specifications of components of the container (including the name of the approved producers) should be given. Specifications of any radiation shielding of the finished products should also be given. For some radiopharmaceuticals, it is difficult to distinguish between control of starting materials and control of the finished product. For such products, all the information should preferably be placed in the section “Control tests on the finished product”. 2.4 Control tests on the finished product For products intended for intrathecal injection, regardless of volume, an appropriate endotoxin test is required unless its omission can be fully and adequately justified. For terminally-sterilised products, process parameter release* (sometimes called parametric release) could well be justified. In the case of an aseptically-assembled product a sterility test is required. For some radiopharmaceuticals it may not be possible to obtain the results of certain tests, e.g. sterility test, pyrogenicity tests, before the product is released. However, these tests should be done as a monitor for the manufacturing process. Potential and actual impurities should be considered not only for any direct effect on the patient but also for their possible influence on the radiochemical purity or biodistribution of the product. 2.5 Stability tests For all radiopharmaceuticals, the shelf life of the product as supplied by the manufacturer should be specified and justified, as should a shelf life after reconstitution where applicable, taking into account radiochemical and radionuclide degradation products. For radiopharmaceutical kits, the shelf life of the prepared product should be defined; in this case, data should be submitted which detail the minimum and maximum levels of radioactivity (and maximum and minimum volumes) and other relevant factors that are recommended for use in the preparation of the product to be administered to the patient. For radiopharmaceuticals prepared in multiple-dose vials, the stability following removal of successive doses should be discussed. * For the purpose of this guideline, process parameter release is defined as “the decision to release a batch of product for sale or supply based on an assessment of measured and recorded information relating to the validation, maintenance, operation and control of a process.” 179 ■ 3AQ20a ____________________________________________________________ 3. Toxicological and Pharmacological Tests It is appreciated that toxicity may be associated with a radiation dose. This toxicity is a consequence of the use of radiopharmaceuticals in diagnosis and the wanted property of radiopharmaceuticals used in therapy. The evaluation of safety and efficacy of radiopharmaceuticals should, therefore, address both general parameters of the medicinal product and radiation dosimetry aspects.